Amadori glucose adducts modulate mesangial cell growth and collagen gene expression

Diabetic serum contains increased concentrations of glycated proteins, which are preferentially transported into the renal glomerulus. We investigated effects of Amadori glucose adducts in serum proteins, the predominant form in which circulating glycated proteins exist in vivo, on glomerular mesangial cells, where the lesion of diabetic nephropathy originates. [3H]-thymidine incorporation by murine mesangial cells was significantly inhibited when cells were grown in the presence of serum glycated by incubation for four days with 28 mM glucose or when cells were cultured in microtiter plates that had been precoated with glycated serum. This effect was prevented by a monoclonal antibody immunoreactive with Amadori adducts in glycated albumin, and unreactive with other glycated serum proteins or with advanced glycation end (AGE) products. Glycated serum stimulated Type IV collagen gene expression and increased Type IV collagen secretion, an effect also prevented by monoclonal antibodies reactive with Amadori adducts in glycated albumin. The glycation-induced changes in proliferation, collagen synthesis and collagen gene expression were observed in media containing normal glucose concentration and were exaggerated in media containing high glucose concentration. The data indicate that Amadori products of glycated serum proteins induce mesangial cell abnormalities that are highly relevant to the pathogenesis of diabetic nephropathy, and that these effects are accentuated when glycated serum proteins are presented in a hyperglycemic milieu. The data also suggest that mesangial cells specifically recognize Amadori adducts in glycated albumin.